FFA-Induced Hypertension and Endothelial Dysfunction

Insulin resistance has been implicated as the central mechanism in the development of several
cardiovascular risk factors including hypertension, diabetes, lipid disorders, and
coagulation disorders. Recent evidence suggests that increased levels of a circulation fat
(free fatty acids or FFAs) are a leading candidate causing insulin resistance. Our
preliminary studies in indicate that, in addition to insulin resistance, the infusion of
Intralipid and heparin to increase FFAs resulted in a significant rise in systolic and
diastolic blood pressure, impaired endothelial (vascular) function, and increased
inflammatory markers in obese African Americans with and without diabetes. The effects of FFA
on insulin action are well established; however, the blood pressure and vascular effects of
FFAs infusion in obese subjects have not been fully investigated. We hypothesize that
observed changes in blood pressure are the result of acute endothelial dysfunction, and/or
increased activation of the autonomic nervous system. No previous studies have attempted to
determine a dose response effect of increasing FFA on blood pressure. In addition, it is not
know if increased FFAs by repeated oral fat load results in similar blood pressure than
intravenous lipid infusion. Accordingly, we propose: 1) a systematic evaluation of the
effects of increasing FFA levels on blood pressure and endothelial (vascular) function, and
2) determine the effects of comparable increases in FFA concentration via intravenous
infusion of Intralipid or by repeated oral fat load on blood pressure, insulin resistance and
endothelial dysfunction in obese subjects.

A group of obese normotensive subjects will be admitted to the Grady Clinical Research Center
or to the Outpatient Research Unit in the Grady Diabetes Clinic on five occasions. In four of
these admissions, research subjects will receive an 8-hour intravenous infusion, in random
order, of increasing Intralipid concentration (10 ml, 20 ml, 40 ml per hour) or normal saline
(40 ml per hour). During the final admission, research subjects will receive an oral liquid
fat diet every 2 hours for 8-hours. The effect of increased FFAs on blood pressure and
endothelial (vascular) function via intravenous infusion and via oral fat load therapy will
be assessed.

Inclusion Criteria:

- Males or females between the ages of 18 and 65 years.

- Definition: obese = BMI ≥ 30 kg/m2

- Blood pressure < 140/80 mm Hg and no prior history of hypertension

Exclusion Criteria:

- History of hypertension or previous history of antihypertensive drug therapy.

- Current tobacco use

- Fasting triglyceride levels > 250 mg/dL during the stabilization period.

- Liver disease (ALT 2.5x > upper limit of normal), or other significant medical or
surgical illness, including myocardial ischemia, congestive heart failure, liver
failure, and infectious processes.

- Serum creatinine ≥1.5 mg/dL for males, or ≥ 1.4 mg/dL for females.

- History of drug or alcohol abuse within the last 5 years.

- Mental condition rendering the subject unable to understand the nature, scope, and
possible consequences of the study.

- Female subjects are pregnant or breast feeding at time of enrollment into the study.